Pharmacological research最新文献

G protein-coupled receptors (GPCRs), widely expressed in the human central nervous system (CNS), perform numerous physiological functions and play a significant role in the pathogenesis of diseases. Consequently, identifying key therapeutic GPCRs targets for CNS-related diseases is garnering immense interest in research labs and pharmaceutical companies. However, using GPCRs drugs for treating neurodegenerative diseases has limitations, including side effects and uncertain effective time frame. Recognizing the rich history of herbal treatments for neurological disorders like stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), modern pharmacological research is now focusing on the understanding of the efficacy of traditional Chinese medicinal herbs and compounds in modulating GPCRs and treatment of neurodegenerative conditions. This paper will offer a comprehensive, critical review of how certain natural products and compounds target GPCRs to treat neurological diseases. Conducting an in-depth study of herbal remedies and their efficacies against CNS-related disorders through GPCRs targeting will augment our strategies for treating neurological disorders. This will not only broaden our understanding of effective therapeutic methodologies but also identify the root causes of altered GPCRs signaling in the context of pathophysiological mechanisms in neurological diseases. Moreover, it would be informative for the creation of safer and more effective GPCR-mediated drugs, thereby establishing a foundation for future treatment of various neurological diseases.

Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.

Aims

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms

Methods

We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted.

Results

Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings.

Conclusions

Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.

Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.

Mitochondria are metabolic hub, and act as primary sites for reactive oxygen species (ROS) and metabolites generation. Mitochondrial Ca²⁺ uptake contributes to Ca²⁺ storage. Mitochondria-organelle interactions are important for cellular metabolic adaptation, biosynthesis, redox balance, cell fate. Organelle communications are mediated by Ca²⁺/ROS signals, vesicle transport and membrane contact sites. The permeability transition pore (PTP) is an unselective channel that provides a release pathway for Ca²⁺/ROS, mtDNA and metabolites. F-ATP synthase inhibitory factor 1 (IF1) participates in regulation of PTP opening and is required for the translocation of transcriptional factors c-Myc/PGC1α to mitochondria to stimulate metabolic switch. IF1, a mitochondrial specific protein, has been suggested to regulate other organelles including nucleus, endoplasmic reticulum and lysosomes. IF1 may be able to mediate mitochondria-organelle interactions and cellular physiology through regulation of PTP activity.

The incidence of cardiometabolic disease is increasing globally, with a trend toward younger age of onset. Among these, atherosclerotic cardiovascular disease is a leading cause of mortality worldwide. Despite the efficacy of traditional lipid-lowering drugs, such as statins, in reducing low-density lipoprotein cholesterol levels, a significant residual risk of cardiovascular events remains, which is closely related to unmet triglyceride (TG) targets. The clinical application of current TG-lowering Western medicines has certain limitations, necessitating alternative or complementary therapeutic strategies. Traditional Chinese medicine (TCM) and plant-derived natural products, known for their safety owing to their natural origins and diverse biological activities, offer promising avenues for TG regulation with potentially fewer side effects. This review systematically summarises the mechanisms of TG metabolism and subsequently reviews the regulatory effects of TCM and plant-derived natural products on TG metabolism, including the inhibition of TG synthesis (via endogenous and exogenous pathways), promotion of TG catabolism, regulation of fatty acid absorption and transport, enhancement of lipophagy, modulation of the gut microbiota, and other mechanisms. In conclusion, through a comprehensive analysis of recent studies, this review consolidates the multifaceted regulatory roles of TCM and plant-derived natural products in TG metabolism and elucidates their potential as safer, multi-target therapeutic agents in managing hypertriglyceridemia and mitigating cardiovascular risk, thereby providing a basis for new drug development.

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor β (ERβ) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERβ activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERβ and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERβ agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERβ. DPN treatment augmented the nuclear accumulation of ERβ and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERβ-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERβ during myogenesis.

Chirality plays a crucial function in the regulation of normal physiological processes and is widespread in organisms. Chirality can be imparted to nanomaterials, whether they are natural or manmade, through the process of asymmetric assembly and/or grafting of molecular chiral groups or linkers. Chiral inorganic nanomaterials possess unique physical and chemical features that set them apart from regular nanomaterials. They also have the ability to interact with cells and tissues in a specific manner, making them useful in various biomedical applications, particularly in the treatment of tumors. Despite the growing amount of research on chiral inorganic nanomaterials in the tumor microenvironment (TME) and their promising potential applications, there is a lack of literature that comprehensively summarizes the intricate interactions between chiral inorganic nanomaterials and TME. In this review, we introduce the fundamental concept, classification, synthesis methods, and physicochemical features of chiral inorganic nanomaterials. Next, we briefly outline the components of TME, such as T cells, macrophages, dendritic cells, and weak acids, and then discuss the anti-tumor effects of several chiral inorganic nanoparticles targeting these components and their potential for possible application during cancer therapy. Finally, the present challenges faced by chiral inorganic nanomaterials in cancer treatment and their future areas of investigation are disclosed.

It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.